Ureas, diastereomeric

Further upgrading by crystallization is possible. Presumably a highly diastereomerically enriched titanium intermediate is formed by chelation with the chiral urea moiety. 

Use of the valine derived (4S )-3-acetyl-4-isopropyl-1,3-oxazolidine (8)92, the C2-symmetric reagents (2.5,55)-l-acetyl-2,5-bissubstituted pyrrolidine 994, or the doubly deprotonated acetyl urea /V-acetyl- V..V -bis[(.S)-l-phcnylethyl]urea (10), also does not lead to sufficient induced stereoselectivity combined with acceptable chemical yield. When the acetyl urea enolate is reacted with aliphatic and aromatic aldehydes, the diastereomeric adducts (ratios ranging from 1 1 to 3 1) may be separated by column chromatography to give ultimately both enantiomers of the 3-hydroxy acids in 99% ee110. 

Since dorzolamide possesses two chiral centers, an indirect chiral separation has been developed [18]. The procedure employs the chemical derivatization of the secondary amino group of the inhibitor, formation of diastereomeric urea derivatives (each with three chiral centers in the molecule), and their separation under non-ehiral HPLC conditions. Using... 

A preparatively useful approach to the enantiomerically pure antihypertensive agent (R)-SQ 32,926 was disclosed by Atwal et al. (Scheme 4.13) [169]. In the first step, the 1,4-dihydropyrimidine intermediate 38 is acylated at N3 with 4-nitrophenyl chloroformate followed by hydrolysis with HC1 in THF to give DHPM 39. Treatment with (R)-a-methylbenzylamine provided a mixture of diastereomeric ureas from which the (R,R) isomer 40 was separated by crystallization. Cleavage with TFA provided (R)-SQ 32,926 in high enantiomeric purity. Similar strategies have been used to obtain a number of pharmacologically important DHPM derivatives in enantiomerically pure form [169, 186, 187]. 

Amphoteric compounds such as amino acids can be resolved as acid or amine forms after deriving corresponding esters or N-acyl compounds. Racemic alcohols and amines are also resolved by use of optically active isocyanates, where the alcohols and amines are derived the corresponding diastereomeric urethanes or ureas. 

If additionally chiral centers (e.g. asymmetric C-atoms, characterized here by D and L) are incorporated into the ether or urea residues two diastereomeric forms of this single tetraurea LA (LAP, LAM) are possible in a dimer due to the orientation of the carbonyl groups (indicated by P and M). Both forms must be present in a homodimer of such a tetraurea and for a heterodimer formed with a normal tetraurea B two diastereomeric forms (LAP-BM, LAM-BP) should exist. Eventually, this additional chiral center could even induce a certain direction of the C=0 groups (e.g. LAP being more stable than LAM, and consequently DAM more stable than DAP). 

In 2002 the same author demonstrated the usefulness of this method in a rather demanding context including an intramolecular cycloaddition with an W-sulfinyl urea as a new type of N-sulfinyl dienophile (Scheme 60) [144]. As key steps in the total synthesis of freshwater cyanobacterial hepatotoxins, ( , )-diene 238 was transformed into N-sulfinyl urea 239 which immediately cycloadds intramolecularly yielding tricycle 240 as a single isomer in excellent yield. After reaction with phenylmagnesium bromide the intermediate allylic sulfoxide rearranges cleanly to diastereomerically pure allylic alcohol... 

It was shown by Shonenberger et al. that thermal decomposition of the separated diastereomeric (a-methylbenzyl) urea derivatives produced by the reaction of [19] and chiral secondary amines is a convenient technique for the retrieval of the optically pure amines (93). 

Ureas 230 were cyclized to 1,2,3,6,7,llfe-hexahydro-4//-pyrimido[6,l-a]isoquinolin-4-ones 231 on the action of diisobutylaluminium hydride followed by treatment with formic acid [84S1071 85H(23)2907]. From 230 (R = = H, R = Me, R = R = valence bond), a diastereomeric... 

The slight difference between the lattice energies of the diastereomeric urea clathrates leads to low ee values and renders the steering of the recrystallization a difficult process which depends strongly on experimental conditions. Therefore, the development of new more universally applicable host substances has largely replaced urea for the resolution of racemates. 

The formation of diastereomeric ureides from chloro-fomnate reagents has been used in quantitative assays and for the preparative separation of both secondary and tertiary amines. Quantitative assays for promethazine, a tertiary amine of the phenothiazine group of pharmaceuticals, have been developed. Maibaum [100] carried out a three-stage reaction in which the racemic promethazine was reacted with vinyl chloroformate and the carbamate was subsequently hydrolysed to the secondary amine. The enantiomeric ratio of the amine was then determined as the urea following reaction with a chiral isocyanate. In a later development, Witte et al. [lOI] directly derivatized the same compound with (— )-menthyl chloroformate (17) and separated the diastereomers by HPLC. (—)-Menthyl chloroformate has also been used to resolve the enantiomers of nomicotine as... 

Chiral derivatization of the amino group has included the formation of diastereomeric amides, ureas, thioureas and isoindoles, the carboxylic acid group being either protected or left unreacted. Diastereomeric dipeptides have been prepared using a range of N-substituted activated amino acids, e.g. S( — )-N-(trifluoroacetyl)propyl chloride (11), L-leucine-N-carboxyanhydride (45) and t-butoxycarbonyl-L-leucine N-hydroxysuednimide ester (55). (See Section 4.6.2 for reagent structures). 

Formation of diastereomeric ureas from chiral carbamate reagents... 

Alak and Armstrong (107,108,112,113) investigated the influence of different silicas and binders on the separation behavior of P-cyclodextrin TLC plates. Besides nine racemates, three diastereomeric compounds and six structural isomers were separated. Wilson (109) impregnated silica plates with a 1% solution of P-CD in ethanol-dimethylsulfoxide (80 20 by volume) racemic mandelic acid was barely separated, and the antipode separation of P-blockers was not possible. Armstrong et al. (110) were the first to describe application of P-cyclodextrin as a chiral eluent additive for separations on reversed-phase TLC plates. The success of separation was strongly dependent on type and quantity of modifier applied, but above all on the concentration of P-CD. The low solubility of 3-CD in water (0.017 M, 2S C) can be improved by addition of urea sodium chloride stabilizes the binder of the RP plates. Compared to 3-CD bonded phases, a reversed retention behavior was noticed, the D-enantiomer eluting above the L-isomer. The separation of steroid epimers and other diastereomeric classes of compounds is also possible with this technique. Hydroxypropyl and hydroxyethyl P-... 

Intensive studies using NMR methods, kinetic experiments, and computational calculations were conducted to elucidate the catalytic mechanism and observed stereoinduction [22]. The data revealed that the hydrocyanation catalyzed by 33 presumably proceed over an initial amido-thiourea catalyzed proton transfer from hydrogen isocyanide to imine 32 to generate a catalyst-bound diastereomeric iminium/cyanide ion pair. Thereby, hydrogen isocyanide, as the tautomeric form of HCN, is stabilized by the thiourea moiety of 33. The stabilization degree of the formed iminium ion by the catalyst is seen as the basis for enantioselectivity. Subsequent collapse of the ion pair and bond formation between the electrophile and the cyanide ion forms the a-amino nitrile. It should be emphasized that the productive catalytic cycle with 33 does not involve a direct imine-urea binding, although this interaction was observed both kinetically and spectroscopically in the Strecker reaction catalyzed by 25 (see above) [19],... 

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